A multicenter phase II trial of neoadjuvant letrozole plus low‐dose cyclophosphamide in postmenopausal patients with estrogen receptor‐positive breast cancer (JBCRG‐07): therapeutic efficacy and clinical implications of circulating endothelial cells

Abstract

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single‐arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2–4 N0–1, and estrogen receptor‐positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti‐angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0–80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast‐conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease‐free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post‐treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post‐treatment). Multivariate analysis showed that post‐treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor‐positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. Clinical trial registration number: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low‐dose metronomic cyclophosphamide for postmenopausal women with endocrine‐responsive breast cancer (JBCRG‐07)

Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression

“…It has been shown to directly result in tumor shrinkage. It is often preferred to chemotherapy due to the fact of its lower toxicity [16]. In hormone therapy, a novel generation of aromatase inhibitors (AIs) limit estrogen production [17].…”

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR

“…This was different from the cellular response to endocrine therapy as endocrine therapy did not increase the expression of the apoptosis-related markers and decreased the expression of M30 in the responders. Therefore, the induction of apoptosis by metronomic chemoendocrine therapy explains, at least in part, the improved efficacy of chemoendocrine therapy compared with endocrine therapy alone [ 13 , 14 ]. In this regard, a response-guided approach in which metronomic chemotherapy is added to the treatment of non-responders to short-term exposure of endocrine therapy is a reasonable option to improve treatment efficacy [ 14 ].…”

“…The design of the clinical trial, JBCRG-07, is described elsewhere (Registration number: UMIN 000001331) [ 13 ]. Briefly, patients with T2-4 N0-1 and estrogen receptor (ER)-positive breast cancer were enrolled between October 2007 and March 2010.…”

“…We have previously shown that the addition of metronomic chemotherapy, an oral cyclophosphamide, to endocrine therapy increases breast-conservation rate with minimal toxicity [ 13 ]. In addition, we reported that a response-guided approach, such as the addition of metronomic cyclophosphamide in patients not responding to an 8–12-week course of endocrine therapy, resulted in a tumor response comparable to that in responders who were treated with endocrine therapy alone [ 14 ].…”

A Snapshot of The Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy

“…In colorectal cancer patients, the quantification of CECs could improve the identification of early predictors of response to bevacizumab combined with FOLFOX (FOL–Folinic acid (leucovorin), F–Fluorouracil (5-FU), OX–Oxaliplatin (Eloxatin)/OXXEL (Oxaliplatin plus Xeloda) [181]. Similarly, other studies have assessed the predictive value of CECs for anticancer therapies in urothelial [201], breast [202], lung [203] and renal carcinoma [204].…”